Parafibromin and APC as Screening Markers for Malignant Potential in Atypical Parathyroid Adenomas

Abstract

The identification of parathyroid carcinomas is based upon histopathological criteria in which an invasive growth pattern or distant metastasis is demonstrated. A dilemma arises when tumours present with atypical histopathological features but lack direct evidence of malignancy. Recently, reduced expression or loss of the tumour suppressor proteins parafibromin and adenomatous polyposis coli (APC) has been associated with parathyroid malignancy. We report results from APC and parafibromin expression analyses by immunohistochemistry and Western blot in five cases of atypical adenoma, a single case of carcinoma and 54 adenomas without atypical features. Complete loss of APC immunoreactivity and reduced expression of parafibromin was evident in two of the atypical adenomas and in the parathyroid carcinoma. By contrast, all adenomas displayed APC expression, including two cases with hyperparathyroidism 2 gene (HRPT2) mutations and loss of parafibromin expression. We conclude that loss of APC is a frequent molecular event in atypical adenomas and carcinomas, but not in adenomas. Following verification in an independent material, APC could become a valuable tool when assessing parathyroid tumours in the clinical setting. Furthermore, the molecular resemblance of atypical adenomas with carcinoma concerning parafibromin and APC expression indicates that atypical adenomas should be subjects to watchful follow-up.

Clinicopathological correlates of hyperparathyroidism

“…However, with recent developments in molecular pathology and ancillary tools, the classification of these borderline tumours has been greatly refined 153. When used in the appropriate clinical and pathological setting, ancillary biomarkers serve a crucial role in the distinction of malignancy in these borderline tumours, thereby enhancing the accuracy of the pathological examination 38 42 43 45 46 98 99 155 156 158–161…”

“…Based on the currently available evidence and our own experiences , loss-of-expression of retinoblastoma protein (Rb), Bcl-2a, p27, parafibromin, mdm2 and APC, as well as increased MIB-1 (Ki67) proliferative index >5%, overexpression of p53 and positivity for galectin-3 (in the absence of multiglandular disease) favours a diagnosis of malignancy in a parathyroid neoplasm with worrisome histopathological features 31 33 38 42–46 49 87 98 99 141 153 155 156 158–164. In particular, the use of parafibromin immunostain (figure 8E) is very helpful to differentiate between parathyroid adenomas (intact nuclear and nucleolar parafibromin expression) and parathyroid carcinomas (complete loss of nuclear or nucleolar parafibromin expression) 38 42 43 46 98 99 153 156 159 161 162. Recently, routine assessment of parafibromin staining has been proposed in all parathyroid carcinomas to help select patients for genetic testing and to predict prognosis: those with parafibromin-negative parathyroid carcinomas had a significantly higher risk of recurrence, a decreased 5-year survival of 59% and a decreased 10-year survival of 23%, which may warrant closer surveillance 47 158 162…”

Parathyroid Carcinoma

“…61 Parafibromin is also localized in the nucleolus. Three nucleolar localization signals at residues [76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][192][193][194], and 393-409 have been identified. 63 The role of parafibromin as a tumor suppressor protein comes from the observation that parathyroid tumors carrying CDC73 mutations are frequently associated with loss of parafibromin expression.…”

“…CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM diagnostic utility. 49,51,64,88 The combined finding of negative parafibromin staining and CDC73 gene mutations increases the likelihood of malignancy and also has predictive value regarding the clinical outcome. [49][50][51][52] Indeed, in a recent study we showed that loss of parafibromin staining, and, to a lesser extent, the presence of a CDC73 mutation, predicts malignant behavior, namely, the occurrence of local invasion and/or metastases and increased mortality.…”

Menin and bone metabolism

“…Overexpression of cyclin D1 is related to the development of parathyroid adenoma [19,20]. The retinoblastoma protein and parafibromin may be related to the pathogenesis of parathyroid carcinoma [21,22]. As for the MEN1 gene, somatic biallelic inactivating MEN1 gene defects occur in up to 20 % of sporadic parathyroid adenomas [23].…”